Wednesday, December 31, 2014

Top HCV stories of 2014
Hepatitis C virus infection entered a new era this year, following FDA approvals of multiple treatment regimens, and new, groundbreaking clinical data produced by the top researchers in the field. Using web analytics, social media and expert opinion, Healio.com/Hepatology has compiled a list of some of the most important, relevant research and news on hepatitis C virus infection presented during the past year.FDA approves Harvoni for HCV treatment

Using the breakthrough therapy designation, the FDA approved the first combination pill for treatment of chronic hepatitis C virus genotype 1 that does not require interferon or ribavirin for administration.

Treatment-naive participants showed a 94% sustained virologic response rate after 8 weeks of treatment and a 96% SVR rate after 12 weeks. Treatment-naive patients with and without cirrhosis showed a 99% SVR rate after 12 weeks. Among treatment-experienced participants with and without cirrhosis, ribavirin did not improve response rates in any of the trials.

The FDA approved a treatment for patients with hepatitis C virus genotype 1 infection, including those with cirrhosis.

“The new generation of therapeutics for hepatitis C virus is changing the treatment paradigm for Americans living with the disease,” Edward Cox, MD, MPH, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research, said in a press release. “We continue to see the development of new all-oral treatments with very high virologic response rates and improved safety profiles compared to some of the older interferon-based drug regimens.”

CHICAGO — When it comes to the latest HCV regimens, so-called “special” patient populations may have to accept the fact that they are actually quite ordinary.

“Special populations are no longer special,” said Nancy S. Reau, MD, assistant professor of medicine at the University of Chicago, and HCV Next Editorial Board member, during a presentation. “Sorry, you don’t get to have special privileges anymore — you’re just as generic as the rest of us.”Read moreHCV predicted to become rare by 2036

Hepatitis C virus could become a rare disease in the next 22 years, as a result of recently approved, highly effective new therapies.

“Making hepatitis C (HCV) a rare disease would be a tremendous, life-saving accomplishment,” Mina Kabiri, doctoral student at the University of Pittsburgh Graduate School of Public Health, and study co-investigator, said in a press release. “However, to do this, we will need improved access to care and increased treatment capacity, primarily in the form of primary care physicians who can manage the care of infected people identified through increased screening.”

BOSTON — A fixed-dose combination involving the novel compound BMS-791325 was associated with SVR12 rates of around 90% in treatment-naive and experienced patients, according to findings from the UNITY trials series presented at The Liver Meeting.

“Current treatments for treatment experienced patients with cirrhosis require 24 weeks,” Andrew J. Muir, MD, of the Duke Clinical Research Institute at the Duke University School of Medicine in North Carolina, said. “This study demonstrates that a 12-week regimen can cure this patient group with high SVR rates. Ribavirin was important for the genotype 1a patients to maximize chance of cure.”

Members of the House of Representatives Committee on Energy and Commerce have asked Gilead Sciences Inc. to explain the price for Sovaldi, the company’s recently approved drug to treat hepatitis C virus.

“Our concern is that a treatment will not cure patients if they cannot afford it,” a letter addressed to John C. Martin, PhD, chief executive officer of Gilead Sciences Inc., said. “These costs are likely to be too high for many patients, both those with public insurance and those with private insurance.”Read moreC-WORTHY: Grazoprevir/elbasvir regimen yielded high SVR rates in patients with HCV genotype 1

BOSTON — A number of patients with hepatitis C virus genotype 1 infection, with and without cirrhosis, and patients coinfected with HIV and HCV, achieved sustained virologic response when treated with grazoprevir and elbasvir, according to data presented at The Liver Meeting.

“Grazoprevir and elbasvir, with or without ribavirin, demonstrated high efficacy,” Eric J. Lawitz, MD, of The Texas Liver Institute, University of Texas Health Science Center, San Antonio, said in the hepatitis plenary. “High efficacy was achieved regardless of the presence or absence of ribavirin or extended treatment duration from 12 to 18 weeks.”

CHICAGO — A regimen of three direct-acting antivirals demonstrated high rates of sustained virologic response in hepatitis C virus genotype 1b-infected patients who previously failed treatment with pegylated interferon and ribavirin, according to results from the PEARL-II study, presented at Digestive Disease Week 2014.

“The regimen was generally well-tolerated, as evidenced by the low rate of treatment discontinuation and serious adverse events,” Pietro Andreone, MD, of the University of Bologna in Italy, said during the presentation.

The FDA approved changes to the Olysio label reflecting that it can be used in combination with Sovaldi to treat patients with chronic hepatitis C virus genotype 1 infection.

Olysio (Simeprevir, Janssen Therapeutics) is a NS3/4A protease inhibitor that functions by blocking the viral protease enzyme HCV uses to replicate. It was approved by the FDA in November 2013 as part of an antiviral treatment regimen with pegylated interferon and ribavirin for patients with chronic HCV genotype 1.Read more

New data indicate a rising incidence of hepatitis C infection among young, primarily white, non-urban people who inject drugs.

From 2006 to 2012, there were 7,169 cases of acute hepatitis C reported to the CDC. Among the 7,077 cases with a documented age, 44% were young people. In 2012, 49% of the cases were young people, whereas in 2006, 36% were young people. The majority of the cases were white and non-Hispanic, and the cases were equally among men and women.

LONDON — WHO unveiled its first-ever treatment guidelines for HCV during a press conference at the International Liver Congress, the annual meeting of the European Association for the Study of the Liver.

St. Louis University to test sofosbuvir/ribavirin in pediatric HCV cases

In a multicenter clinical study, researcher Jeffrey Teckman, MD, professor of pediatrics at SLU, will analyze the combination of sofosbuvir (Sovaldi, Gilead Sciences) and ribavirin among children aged 3 to 17 years in an effort to cure the infection while limiting side effects.

LONDON — Multitargeted therapy of ABT-450 with ritonavir, ombitasvir and dasabuvir yielded strong response rates with few discontinuations among patients with cirrhosis and hepatitis C genotype 1 treated for 12 or 24 weeks, according to findings presented at EASL 2014.

“For genotype 1b disease, almost everyone achieved SVR,” HCV Next Editorial Board member Fred Poordad, MD, of The Texas Liver Institute and University of Texas Health Science Center in San Antonio, said. “The rate was almost 100% except for a prior partial responder. “When measured by surrogates of portal hypertension and hepatic function, high SVR rates were achieved with no appreciable difference between either arm.”

BOSTON — Sustained virologic response rates of nearly 100% were reported in a multiple-drug combination with or without ribavirin, according to findings presented here at the 2014 Conference on Retroviruses and Opportunistic Infections.

Researchers with the PEARL-III study investigated three drugs from AbbVie with or without ribavirin for non-cirrhotic, treatment-naive hepatitis C virus genotype 1b disease: the protease inhibitor ABT-450/r, which is dosed with ritonavir 100 mg; the NS5A inhibitor ABT-267; and the non-nucleoside polymerase inhibitor ABT-333.

The hepatitis C virus has a profound negative impact on patients’ quality of life, both in its clinical manifestations and its overall economic burden.

A panel of hepatologists, experienced with evidence assessment, was convened to estimate how HCV affects patient outcomes. The researchers used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology.

2014 has been a year of both opportunities and challenges in the fight against viral hepatitis. In May, the World Health Assembly passed a new resolution [PDF 151 KB] on viral hepatitis, urging member states to develop and implement coordinated, national strategies for preventing, diagnosing and treating viral hepatitis. Our nation’s own comprehensive viral hepatitis strategy, the Action Plan for the Prevention, Care, and Treatment of Viral Hepatitis (Action Plan) [PDF 2 MB] was updated for three more years (2014-2016) and released in April 2014—extending our national commitment to the original 2011 goal of combating the silent epidemic of viral hepatitis. Also of consequence, the full implementation of the Affordable Care Act at the start of the year paved the way for unprecedented access to medical care and opened doors for increased screening, diagnosis, and treatment of viral hepatitis, as well as vaccination against hepatitis A (HAV) and hepatitis B (HBV).

Monday, December 29, 2014

The Health Care Authority (HCA) has issued an interim updated hepatitis C policy that reflects the rapidly changing field of treatment for the chronic disease. The policy will be presented to the Washington State Drug Utilization Board for final approval in February.

There are several key updates in the policy, which applies to Medicaid clients.

Those infected with hepatitis B or HIV now qualify for hepatitis C treatment if they have moderate liver scarring. In the previous policy, only those with severe liver disease and other specific conditions, including those receiving an organ transplant, qualified for the treatment.

People with a history of intravenous drug use may be treated right away if they meet the treatment qualifications. In the previous policy, individuals had to have not used IV drugs for the past six months, with few exceptions.

The policy provides guidance on when it is not appropriate to offer hepatitis C treatment.

HCA began reviewing the hepatitis C policy after a new treatment came on the market in December 2013. Another treatment was approved by the Federal Drug Administration in October.

“The field of hepatitis C treatment is changing rapidly—we needed a more robust policy that reflected current treatment and research and gives the treating provider more information to make decisions,” said HCA Chief Medical Officer Dr. Dan Lessler. “We included experts and advocates in this process, and the policy is stronger as a result.”

Hepatitis C is a virus that can lead to chronic liver disease, including liver damage, cirrhosis, liver failure or liver cancer. According to the U.S. Centers for Disease Control, about 17,000 Americans become infected with hepatitis C each year.

FOSTER CITY, Calif.--(BUSINESS WIRE)--Dec. 29, 2014-- Gilead Sciences, Inc. (Nasdaq:GILD) today announced an expansion to its agreement with Janssen R&D Ireland for the development and commercialization of a new once-daily single tablet regimen containing Gilead's tenofovir alafenamide (TAF) and emtricitabine, and Janssen's rilpivirine.

The original agreement was established in 2009 for the development and commercialization of Complera®, marketed as Eviplera® in the European Union, which combines tenofovir disoproxil fumarate, emtricitabine and rilpivirine in a once-daily tablet. Gilead will initiate Phase 3 studies of emtricitabine/rilpivirine/TAF in the coming months. Pending the product's approval, Gilead will be responsible for the manufacturing, registration, distribution and commercialization of the regimen in most countries, while Janssen will distribute in approximately 17 markets.

TAF is a novel nucleotide reverse transcriptase inhibitor that has demonstrated high antiviral efficacy at a dose 10 times lower than Gilead's Viread® (tenofovir disoproxil fumarate), as well as an improved renal and bone safety profile.

"We believe that TAF's efficacy and safety advantages may make it a strong backbone of new fixed-dose combinations and single tablet regimens," said Norbert Bischofberger, PhD, Executive Vice President, Research and Development and Chief Scientific Officer, Gilead Sciences. "Gilead is pleased to continue its collaboration with Janssen to bring improved treatment options to patients living with HIV."

Gilead and Janssen also have amended a licensing agreement for the development and commercialization of a once-daily single tablet regimen for HIV containing Gilead's TAF, emtricitabine and cobicistat, and Janssen's darunavir.

Under the amended agreement, Janssen will be responsible for further development of the regimen and, subject to regulatory approval, the manufacturing, registration, distribution and commercialization of the product worldwide.

Separate to the Janssen agreements, Gilead is advancing its own TAF-based single tablet regimen containing elvitegravir, cobicistat, emtricitabine and TAF. The company announced on November 6, 2014, it filed for regulatory approval in the United States.

TAF and TAF-based regimens are investigational products in the United States and have not yet been determined safe or efficacious in humans.

U.S. full prescribing information for Complera and Viread is available at www.gilead.com.

Sunday, December 28, 2014

Lille (France), Boston (Massachusetts, United States), December 16, 2014 – GENFIT (Euronext: GNFT; ISIN: FR0004163111), a biopharmaceutical company at the forefront of developing therapeutic and diagnostic solutions in metabolic and inflammatory diseases, that notably affect the liver or the gastrointestinal system, today announces that a recent study provides new
evidence for anti-cirrhotic effects of GFT505 in the context of NASH.

The aim of NASH treatment is to eliminate the pathology responsible for the development of fibrosis, and to prevent disease evolution to cirrhosis and its complications. In the model used for this study (Wistar rats fed a cholinedeficient L-amino acid-defined (CDAA) diet + 1% cholesterol for 11 weeks), NASH is associated with the development of marked hepatic fibrosis that can progress to cirrhosis.
In this study, one group was treated with GFT505 and the results compared to those of the control group. The efficacy of GFT505 on NASH was assessed according to the same diagnostic criteria applied to the ongoing Phase 2b clinical study (GFT505-212-7: GOLDEN-505). Fibrosis was evaluated according to the scale classically used in the clinic, from Stage 0 (no fibrosis) to Stage 4
(cirrhosis).

While 91% of the control group developed NASH, only 25% of the group treated with GFT505 had NASH at the end of the treatment period.

The analysis reveals that these anti-NASH effects of GFT505 are essentially due to a complete inhibition of the necrotic and inflammatory process.

Importantly, more than 90% of the control group developed advanced fibrosis (Stage 3) or cirrhosis (Stage 4), but no such cases were observed in the group treated with GFT505.

This data is essential since it shows that NASH treatment by GFT505 is accompanied by a blockage of the fibrotic process, resulting in protection against evolution to cirrhosis. This study alone meets all the criteria for an efficient NASH treatment in man, the ultimate aim being to protect patients from severe hepatic complications that can lead to liver transplantation or death. Complementary studies are in progress to better understand the mechanism of action of GFT505 in this model, and a scientific manuscript will be submitted for publication in 2015.»

About GENFIT:
GENFIT is a biopharmaceutical company focused on the Discovery and Development of drug candidates in fields of high medical need due to a lack of suitable treatment and an increasing number of patients worldwide.

GENFIT’s R&D efforts are focused on contributing to bringing new medicines to market for patients with metabolic, inflammatory, autoimmune and fibrotic diseases, that affect the liver (such as NASH - Nonalcoholic steatohepatitis) or the bowel (such as the inflammatory bowel disease). GENFIT implements mutually beneficial approaches that combine novel treatments and biomarkers; its research programs have resulted in the creation of a rich and diversified pipeline of drug candidates, including GENFIT’s lead proprietary compound, GFT505, that is completing a Phase 2b study in NASH.

With facilities in Lille, France, and Boston, MA (USA), the Company has approximately 80 employees. GENFIT is a public company listed in compartment B of Euronext’s regulated market in Paris (Euronext: GNFT; ISIN: FR0004163111).

Disclaimer: This press release contains certain forward-looking statements. Although the Company believes its expectations are based on reasonable assumptions, these forward-looking statements are subject to numerousrisks and uncertainties, which could cause actual results to differ materially from those anticipated. For a discussion of risks and uncertainties which could cause the Company's actual results, financial condition, performance or achievements to differ from those contained in the forward-looking statements, please refer to the Risk Factors (“Facteurs de Risque") section of the Listing Prospectus upon the admission of Company’s shares for trading on the regulated market Euronext of Euronext Paris filed with the AMF, which is available on the AMF website (www.amf-france.org) or on GENFIT’s website (www.genfit.com).

This press release and the information contained herein do not constitute an offer to sell or a solicitation of an offer to buy or subscribe to shares in GENFIT in any country.

There is little mystery that HCV therapy has been central to my career. Beginning with recombinant interferon trials for HBV and NANB in the mid-80s, to the discovery of HCV by Chiron in 1989, through multiple clinical trials in the 1990s and early 2000s, and finally to the miracle of direct-acting antiviral agents over the past decade, it has been a phenomenal ride. I have been awed by the courage of my patients who suffered through the interferon days, and now join them in their joy at being cured without interferon. The past 25 years have witnessed a remarkable success story — one with industry and academic centers cooperating to bring this miracle to millions of patients...Case Challenges

A 24-year-old white female with hepatitis C virus from IV drug abuse, depression and herpes simplex virus infection was referred to the liver clinic by her primary care doctor due to significant interim elevations in her liver-associated enzymes from a normal baseline 6 months earlier.

Cover Story

Diabetes and HCV: Unraveling a Complicated RelationshipSome research suggests that curing HCV would reduce the likelihood of developing diabetes, that controlling diabetes would improve HCV outcomes, and that adequately treating one condition would allow the other to be more manageable. In conflict with those studies, recent study data published in Hepatology suggested no association between HCV and diabetes.

The Liver Meeting 2014HCV Next had the opportunity to sit down with leading experts in the field while onsite at The Liver Meeting. They each provided insight into the data presented and how it will impact care of patients with HCV

Chronic infection with hepatitis C virus remains the leading indication for liver transplantation in the United States. As the prevalence of cirrhosis and hepatocellular carcinoma attributed to HCV infection are expected to rise during the next 2 decades, HCV will continue to be a major source of morbidity and will contribute to a growing health care burden associated with advanced chronic liver disease.

CLEVELAND -- There are plenty of wives' tales for preventing and fighting colds and flu. Which are true and which aren't?

Chicken Soup: Plenty of moms have made chicken soup to help fight off a cold's effects and, it turns out, mom knows best. "Chicken soup works!" says Roy Buchinsky, MD, Director of Wellness at University Hospitals (UH) Case Medical Center. "It works as an anti-inflammatory, it boosts the immune system, and can help with nasal congestion." Chicken soup workst: TRUE!

Feed a Cold, Starve a Fever: "You should eat whether you have a fever or a cold," says Dr. Buchinsky. "Eating enhances your immunity to fight off infections." Dr. Buchinsky says before modern medicine, people believed colds thrived when your body temperature was low and therefore your immunity was low so eating was recommended to increase a body's internal thermostat and raise immunity. That part of the equation has merit. People also believed by not eating, you could lower the body's temperature to lower a fever. That part of the equation is incorrect. Dr. Buchinsky says eating healthy helps regardless of whether you have a cold or a fever. FALSE!

Vitamin C: "Studies have shown there is no benefit of vitamin C in the normal population in preventing colds," says Dr. Buchinsky. It might help, however, with the elderly, the immune-suppressed, and for people with poor diets. MOSTLY FALSE!

Sound bites from Roy Buchinsky, MD, Director of Wellness at UH Case Medical Center in Cleveland, Ohio, and related b-roll are also available for download on http://news.uhhospitals.org/.

Thursday, December 25, 2014

AbbVie has won the exclusive rights for their newly approved Viekira Pak drug for Hepatitis C treatment. In order to win an exclusive deal with Express Script, the largest manager of prescription drug manager in USA, AbbVie cut the price of their drug. In an announcement on Monday, Express Script decided to go with the AbbVie`s Viekira Park treatment for hepatitis C genotype-1. According to the deal Express will exclude Gilead’s ledipasvir/sofosbuvir combo (Harvoni) and Janssen Therapeutics’ simeprevir (Olysio). This is a welcome news for both doctor and patient as Express Script decided to provide the medicine to a patient regardless of the stage of Hepatitis C the patient is carrying.

Critics are saying that though, Viekira is less expensive but a patient has to take the medicine three times a day, where as they had to take the other mentioned two medicines just once. Gilead`s Single drug treatment Sovaldi (sofosbuvir) is priced at $84,000, or $1,000 per pill for a 12-week treatment for now. As for the Viekira Pak (a combination of ombitasvir, dasabuvir, paritaprevir, and ritonavir) was $83,319, but with the new deal Express Script will be able to offer the drug for around $51,000-$66,000. From January 1st Express Script will stop offering Gilead`s Single drug treatment Sovaldi to its patients.

In a statement Steve Miller, MD, Senior Vice President and Chief Medical Officer of Express Scripts said, “For the first time, a pharmaceutical manufacturer and a pharmacy benefit manager has created an agreement to deliver on the promise of a curative therapy for hepatitis C patients”. He then added, “Pharmaceutical innovation must be rewarded based on the value it brings to patients and payers. This agreement marks a fundamental change in how sustainable access and affordability will be delivered to hepatitis C patients”.

But in a statement Express Script said they will provide Sovaldi, Harvoni and Olysio, for those patients who have already began the treatment. It will also be made available for those patients with other hepatitis C genotypes who have advanced liver diseases.

Tuesday, December 23, 2014

On December 19, 2014, FDA approved VIEKIRA Pak (ombitasvir, paritaprevir, ritonavir fixed dose combination tablets copackaged with dasabuvir tablets) for use with or without ribavirin for the treatment of patients with genotype 1 chronic hepatitis C virus (HCV) infection including those with compensated cirrhosis.

VIEKIRA PAK is not recommended for use in patients with decompensated liver disease.
VIEKIRA PAKs efficacy was evaluated in six clinical trials enrolling 2,308 participants with chronic HCV infection with and without cirrhosis.

The recommended oral dosage of VIEKIRA PAK is two ombitasvir, paritaprevir, ritonavir tablets once daily (in the morning) and one dasabuvir tablet twice daily (morning and evening). Take VIEKIRA PAK with a meal without regard to fat or calorie content

VIEKIRA PAK is used in combination with ribavirin (RBV) in certain patient populations (see Table 1). When administered with VIEKIRA PAK, the recommended dosage of RBV is based on weight: 1000 mg for subjects ≤75 kg and 1200 mg/day for those more than 75 kg, divided and administered twice-daily with food. For ribavirin dosage modifications, refer to the ribavirin prescribing information.
For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in Table 1. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs.
Monitor liver chemistry tests before initiating and during therapy

Table 1. Treatment Regimen and Duration by Patient Population (Treatment-Naïve or Interferon-Experienced)

Patient Population

Treatment*

Duration

Genotype 1a,without cirrhosis

VIEKIRA PAK + ribavirin

12 weeks

Genotype 1a,with cirrhosis

VIEKIRA PAK + ribavirin

24 weeks**

Genotype 1b, without cirrhosis

VIEKIRA PAK

12 weeks

Genotype 1b, with cirrhosis

VIEKIRA PAK + ribavirin

12 weeks

*Note: Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection.
**VIEKIRA PAK administered with ribavirin for 12 weeks may be considered for some patients based on prior treatment history [see Clinical Studies (14.3)].

If VIEKIRA PAK is administered with ribavirin, the contraindications to ribavirin also apply to this combination regimen. Refer to the ribavirin prescribing information for a list of contraindications for ribavirin.

VIEKIRA PAK is contraindicated in patients with severe hepatic impairment due to risk of potential toxicity. VIEKIRA PAK is contraindicated with:

Drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events.

Drugs that are strong inducers of CYP3A and CYP2C8 and may lead to reduced efficacy of VIEKIRA PAK.Drugs that are strong inhibitors of CYP2C8 and may increase dasabuvir plasma concentrations and the risk of QT prolongation.

Table 2 lists drugs that are contraindicated with VIEKIRA PAK.

Table 2. Drugs that are Contraindicated with VIEKIRA PAK

Drug Class

Drug(s) within Class that are Contraindicated

Clinical Comments

Alpha1-adrenoreceptor antagonist

Alfuzosin HCL

Potential for hypotension.

Anticonvulsants

Carbamazepine, phenytoin, phenobarbital

Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of VIEKIRA PAK.

Antihyperlipidemic agent

Gemfibrozil

Increase in dasabuvir exposures by 10-fold which may increase the risk of QT prolongation.

Antimycobacterial

Rifampin

Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of VIEKIRA PAK.

Ergot derivatives

Ergotamine, dihydroergotamine,
ergonovine, methylergonovine

Acute ergot toxicity characterized by vasospasm and tissue ischemia has been associated with co-administration of ritonavir and ergonovine, ergotamine, dihydroergotamine, or methylergonovine.

Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of VIEKIRA PAK.

HMG-CoA Reductase Inhibitors

Lovastatin, simvastatin

Potential for myopathy including rhabdomyolysis.

Neuroleptics

Pimozide

Potential for cardiac arrhythmias.

Non-nucleoside reverse transcriptase inhibitor

Efavirenz

Co-administration of efavirenz based regimens with paritaprevir, ritonavir plus dasabuvir was poorly tolerated and resulted in liver enzyme elevations.

Phosphodiesterase-5 (PDE5) inhibitor

Sildenafil when dosed as REVATIO for the treatment of pulmonary arterial hypertension (PAH)

There is increased potential for sildenafil-associated adverse events such as visual disturbances, hypotension, priapism, and syncope.

Sedatives/hypnotics

Triazolam
Orally administered midazolam

Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam or orally administered midazolam with VIEKIRA PAK may cause large increases in the concentration of these benzodiazepines. The potential exists for serious and/or life threatening events such as prolonged or increased sedation or respiratory depression.

VIEKIRA PAK is contraindicated in patients with known hypersensitivity (e.g. toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir.

WARNINGS AND PRECAUTIONS Increased Risk of ALT Elevations
During clinical trials with VIEKIRA PAK with or without ribavirin, elevations of ALT to greater than 5 times the upper limit of normal (ULN) occurred in approximately 1% of all. ALT elevations were typically asymptomatic, occurred during the first 4 weeks of treatment, and declined within two to eight weeks of onset with continued dosing of VIEKIRA PAK with or without ribavirin.
These ALT elevations were significantly more frequent in female subjects who were using ethinyl estradiol-containing medications such as combined oral contraceptives, contraceptive patches or contraceptive vaginal rings. Ethinyl estradiol-containing medications must be discontinued prior to starting therapy with VIEKIRA PAK.Alternative methods of contraception (e.g, progestin only contraception or non-hormonal methods) are recommended during VIEKIRA PAK therapy. Ethinyl estradiol-containing medications can be restarted approximately 2 weeks following completion of treatment with VIEKIRA PAK.
Women using estrogens other than ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone replacement therapy had a rate of ALT elevation similar to those not receiving any estrogens; however, due to the limited number of subjects taking these other estrogens, caution is warranted for co-administration with VIEKIRA PAK.
Hepatic laboratory testing should be performed during the first 4 weeks of starting treatment and as clinically indicated thereafter. If ALT is found to be elevated above baseline levels, it should be repeated and monitored closely:

Patients should be instructed to consult their health care professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces.

Discontinue VIEKIRA PAK if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR.

Risks Associated With Ribavirin Combination Treatment
If VIEKIRA PAK is administered with ribavirin, the warnings and precautions for ribavirin, in particular the pregnancy avoidance warning, apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of the warnings and precautions for ribavirin.Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions
The concomitant use of VIEKIRA PAK and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to:

Loss of therapeutic effect of VIEKIRA PAK and possible development of resistance

See Table 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during VIEKIRA PAK therapy; review concomitant medications during VIEKIRA PAK therapy; and monitor for the adverse reactions associated with the concomitant drugs.Risk of HIV-1 Protease Inhibitor Drug Resistance in HCV/HIV-1 Co-infected Patients
The ritonavir component of VIEKIRA PAK is also an HIV-1 protease inhibitor and can select for HIV-1 protease inhibitor resistance-associated substitutions. Any HCV/HIV-1 co-infected patients treated with VIEKIRA PAK should also be on a suppressive antiretroviral drug regimen to reduce the risk of HIV-1 protease inhibitor drug resistance.

ADVERSE REACTIONS
If VIEKIRA PAK is administered with ribavirin (RBV), refer to the prescribing information for ribavirin for a list of ribavirin-associated adverse reactions.
The following adverse reaction is described below and elsewhere in the labeling:

Increased Risk of ALT Elevations

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of VIEKIRA PAK cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety assessment was based on data from six Phase 3 clinical trials in more than 2,000 subjects who received VIEKIRA PAK with or without ribavirin for 12 or 24 weeks.

VIEKIRA PAK with Ribavirin in Placebo-Controlled Trials
The safety of VIEKIRA PAK in combination with ribavirin was assessed in 770 subjects with chronic HCV infection in two placebo-controlled trials (SAPPHIRE-I and -II). Adverse reactions that occurred more often in subjects treated with VIEKIRA PAK in combination with ribavirin compared to placebo were fatigue, nausea, pruritus, other skin reactions, insomnia, and asthenia (see Table 3). The majority of the adverse reactions were mild in severity. Two percent of subjects experienced a serious adverse event (SAE). The proportion of subjects who permanently discontinued treatment due to adverse reactions was less than 1%.

Table 3. Adverse Reactions with more than 5% Greater Frequency Reported in Subjects with Chronic HCV GT1 Infection Treated with VIEKIRA PAK in Combination with Ribavirin Compared to Placebo for 12 Weeks

VIEKIRA PAK with and without Ribavirin in Regimen-Controlled Trials
VIEKIRA PAK with and without ribavirin was assessed in 401 and 509 subjects with chronic HCV infection, respectively, in three clinical trials (PEARL-II, PEARL-III and PEARL-IV). Pruritus, nausea, insomnia, and asthenia were identified as adverse events occurring more often in subjects treated with VIEKIRA PAK in combination with ribavirin (see Table 4). The majority of adverse events were mild to moderate in severity. The proportion of subjects who permanently discontinued treatment due to adverse events was less than 1% for both VIEKIRA PAK in combination with ribavirin and VIEKIRA PAK alone.

*Grouped term pruritus included the preferred terms pruritus and pruritus generalized.

VIEKIRA PAK with Ribavirin in Subjects with Compensated Cirrhosis
VIEKIRA PAK with ribavirin was assessed in 380 subjects with compensated cirrhosis who were treated for 12 (n=208) or 24 (n=172) weeks duration (TURQUOISE-II).The type and severity of adverse events in subjects with compensated cirrhosis was comparable to non-cirrhotic subjects in other phase 3 trials. Fatigue, skin reactions and dyspnea occurred at least 5% more often in subjects treated for 24 weeks. The majority of adverse events occurred during the first 12 weeks of dosing in both treatment arms. Most of the adverse events were mild to moderate in severity. The proportion of subjects treated with VIEKIRA PAK for 12 and 24 weeks with SAEs was 6% and 5%, respectively and 2% of subjects permanently discontinued treatment due to adverse events in each treatment arm.Skin Reactions
In PEARL-II, -III and -IV, 7% of subjects receiving VIEKIRA PAK alone and 10% of subjects receiving VIEKIRA PAK with ribavirin reported rash-related events. In SAPPHIRE-I and -II 16% of subjects receiving VIEKIRA PAK with ribavirin and 9% of subjects receiving placebo reported skin reactions. In TURQUOISE-II, 18% and 24% of subjects receiving VIEKIRA PAK with ribavirin for 12 or 24 weeks reported skin reactions. The majority of events were graded as mild in severity. There were no serious events or severe cutaneous reactions, such as Stevens Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), erythema multiforme (EM) or drug rash with eosinophilia and systemic symptoms (DRESS).Laboratory AbnormalitiesSerum ALT Elevations
Approximately 1% of subjects treated with VIEKIRA PAK experienced post-baseline serum ALT levels greater than 5 times the upper limit of normal (ULN) after starting treatment. The incidence increased to 25% (4/16) among women taking a concomitant ethinyl estradiol containing medication. The incidence of clinically relevant ALT elevations among women using estrogens other than ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone replacement therapy was 3% (2/59).

ALT elevations were typically asymptomatic, generally occurred during the first 4 weeks of treatment (mean time 20 days, range 8-57 days) and most resolved with ongoing therapy. The majority of these ALT elevations were assessed as drug-related liver injury. Elevations in ALT were generally not associated with bilirubin elevations. Cirrhosis was not a risk factor for elevated ALT.Serum Bilirubin Elevations

Post-baseline elevations in bilirubin at least 2 x ULN were observed in 15% of subjects receiving VIEKIRA PAK with ribavirin compared to 2% in those receiving VIEKIRA PAK alone. These bilirubin increases were predominately indirect and related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and ribavirin-induced hemolysis. Bilirubin elevations occurred after initiation of treatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were not associated with serum ALT elevations.Anemia/Decreased Hemoglobin Across all Phase 3 studies, the mean change from baseline in hemoglobin levels in subjects treated with VIEKIRA PAK in combination with ribavirin was -2.4 g/dL and the mean change in subjects treated with VIEKIRA PAK alone was -0.5 g/dL. Decreases in hemoglobin levels occurred early in treatment (Week 1-2) with further reductions through Week 3. Hemoglobin values remained low during the remainder of treatment and returned towards baseline levels by post-treatment Week 4. Less than 1% of subjects treated with VIEKIRA PAK with ribavirin had hemoglobin levels decrease to less than 8.0 g/dL during treatment. Seven percent of subjects treated with VIEKIRA PAK in combination with ribavirin underwent a ribavirin dose reduction due to a decrease in hemoglobin levels; three subjects received a blood transfusion and five required erythropoietin. One patient discontinued therapy due to anemia. No subjects treated with VIEKIRA PAK alone had a hemoglobin level less than 10 g/dL.

VIEKIRA PAK in HCV/HIV-1 Co-infected Subjects

VIEKIRA PAK with ribavirin was assessed in 63 subjects with HCV/HIV-1 co-infection who were on stable antiretroviral therapy. The most common adverse events occurring in at least 10% of subjects were fatigue (48%), insomnia (19%), nausea (17%), headache (16%), pruritus (13%), cough (11%), irritability (10%), and ocular icterus (10%).
Elevations in total bilirubin greater than 2 x ULN (mostly indirect) occurred in 34 (54%) subjects. Fifteen of these subjects were also receiving atazanavir at the time of bilirubin elevation and nine also had adverse events of ocular icterus, jaundice or hyperbilirubinemia. None of the subjects with hyperbilirubinemia had concomitant elevations of aminotransferases. No subject experienced a grade 3 ALT elevation.

Seven subjects (11%) had at least one post-baseline hemoglobin value of less than 10 g/dL, and six of these subjects had a ribavirin dose modification; no subject in this small cohort required a blood transfusion or erythropoietin.
Median declines in CD4+ T-cell counts of 47 cells/mm3 and 62 cells/mm3 were observed at the end of 12 and 24 weeks of treatment, respectively, and most returned to baseline levels post-treatment. Two subjects had CD4+ T-cell counts decrease to less than 200 cells/mm3 during treatment without a decrease in CD4%. No subject experienced an AIDS-related opportunistic infection.

VIEKIRA PAK in Selected Liver Transplant Recipients

VIEKIRA PAK with ribavirin was assessed in 34 post-liver transplant subjects with recurrent HCV infection. Adverse events occurring in more than 20% of subjects included fatigue 50%, headache 44%, cough 32%, diarrhea 26%, insomnia 26%, asthenia 24%, nausea 24%, muscle spasms 21% and rash 21%. Ten subjects (29%) had at least one post-baseline hemoglobin value of less than 10 g/dL. Ten subjects underwent a ribavirin dose modification due to decrease in hemoglobin and 3% (1/34) had an interruption of ribavirin. Five subjects received erythropoietin, all of whom initiated ribavirin at the starting dose of 1000 to 1200 mg daily. No subject received a blood transfusion .

DRUG INTERACTIONSPotential for VIEKIRA PAK to Affect Other Drugs
Ombitasvir, paritaprevir, and dasabuvir are inhibitors of UGT1A1, and ritonavir is an inhibitor of CYP3A4. Paritaprevir is an inhibitor of OATP1B1 and OATP1B3 and paritaprevir, ritonavir and dasabuvir are inhibitors of BCRP. Co-administration of VIEKIRA PAK with drugs that are substrates of CYP3A, UGT1A1, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs.

Potential for Other Drugs to Affect One or More Components of VIEKIRA PAK
Paritaprevir and ritonavir are primarily metabolized by CYP3A enzymes. Co-administration of VIEKIRA PAK with strong inhibitors of CYP3A may increase paritaprevir and ritonavir concentrations. Dasabuvir is primarily metabolized by CYP2C8 enzymes. Co-administration of VIEKIRA PAK with drugs that inhibit CYP2C8 may increase dasabuvir plasma concentrations. Ombitasvir is primarily metabolized via amide hydrolysis while CYP enzymes play a minor role in its metabolism. Ombitasvir, paritaprevir, dasabuvir and ritonavir are substrates of P-gp. Ombitasvir, paritaprevir and dasabuvir are substrates of BCRP. Paritaprevir is a substrate of OATP1B1 and OATP1B3. Inhibition of P-gp, BCRP, OATP1B1 or OATP1B3 may increase the plasma concentrations of the various components of VIEKIRA PAK.Established and Other Potential Drug Interactions
If dose adjustments of concomitant medications are made due to treatment with VIEKIRA PAK, doses should be re-adjusted after administration of VIEKIRA PAK is completed. Dose adjustment is not required for VIEKIRA PAK.

Table 5 provides the effect of co-administration of VIEKIRA PAK on concentrations of concomitant drugs and the effect of concomitant drugs on the various components of VIEKIRA PAK. See Contraindications for drugs that are contraindicated with VIEKIRA PAK. Refer to the ritonavir prescribing information for other potentially significant drug interactions with ritonavir.

Table 5. Established Drug Interactions Based on Drug Interaction Trials

Concomitant use of VIEKIRA PAK with inhaled or nasal fluticasone may reduce serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.

DIURETICS

furosemide

furosemide (Cmax)

Clinical monitoring of patients is recommended and therapy should be individualized based on patient’s response.

HIV-ANTIVIRAL AGENTS

atazanavir/ritonavir once daily

paritaprevir

When coadministered with VIEKIRA PAK, atazanavir 300 mg (without ritonavir) should only be given in the morning.

darunavir/ritonavir

↓ darunavir (Ctrough)

Co-administration of VIEKIRA PAK with darunavir/ritonavir is not recommended.

lopinavir/ritonavir

paritaprevir

Co-administration of VIEKIRA PAK with lopinavir/ritonavir is not recommended.

rilpivirine

rilpivirine

Co-administration of VIEKIRA PAK with rilpivirine once daily is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine.

HMG CoA REDUCTASE INHIBITORS

rosuvastatin

rosuvastatin

When VIEKIRA PAK is co-administered with rosuvastatin, the dose of rosuvastatin should not exceed 10 mg per day.

pravastatin

pravastatin

When VIEKIRA PAK is co-administered with pravastatin, the dose of pravastatin should not exceed 40 mg per day.

IMMUNOSUPPRESSANTS

cyclosporine

tacrolimus

cyclosporine

tacrolimus

When initiating therapy with VIEKIRA PAK, reduce cyclosporine dose to 1/5th of the patient’s current cyclosporine dose. Measure cyclosporine blood concentrations to determine subsequent dose modifications. Upon completion of VIEKIRA PAK therapy, the appropriate time to resume pre-VIEKIRA PAK dose of cyclosporine should be guided by assessment of cyclosporine blood concentrations. Frequent assessment of renal function and cyclosporine-related side effects is recommended.
When initiating therapy with VIEKIRA PAK, the dose of tacrolimus needs to be reduced. Do not administer tacrolimus on the day VIEKIRA PAK is initiated. Beginning the day after VIEKIRA PAK is initiated; reinitiate tacrolimus at a reduced dose based on tacrolimus blood concentrations. Typical tacrolimus dosing is 0.5 mg every 7 days.
Measure tacrolimus blood concentrations and adjust dose or dosing frequency to determine subsequent dose modifications. Upon completion of VIEKIRA PAK therapy, the appropriate time to resume pre-VIEKIRA PAK dose of tacrolimus should be guided by assessment of tacrolimus blood concentrations. Frequent assessment of renal function and tacrolimus related side effects is recommended.

LONG ACTING BETA-ADRENOCEPTOR AGONIST

salmeterol

salmeterol

Concurrent administration of VIEKIRA PAK and salmeterol is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.

NARCOTIC ANALGESICS

buprenorphine/naloxone

buprenorphinenorbuprenorphine

No dose adjustment of buprenorphine/naloxone is required upon co-administration with VIEKIRA PAK. Patients should be closely monitored for sedation and cognitive effects.

PROTON PUMP INHIBITORS

omeprazole

↓ omeprazole

Monitor patients for decreased efficacy of omeprazole. Consider increasing the omeprazole dose in patients whose symptoms are not well controlled; avoid use of more than 40 mg per day of omeprazole.

SEDATIVES/HYPNOTICS

alprazolam

alprazolam

Clinical monitoring of patients is recommended. A decrease in alprazolam dose can be considered based on clinical response.

The direction of the arrow indicates the direction of the change in exposures (Cmax and AUC) ( = increase of more than 20%, ↓ = decrease of more than 20%, ↔ = no change or change less than 20%).

Drugs without Clinically Significant Interactions with VIEKIRA PAK
No dose adjustments are recommended when VIEKIRA PAK is co-administered with the following medications: digoxin, duloxetine, emtricitabine/tenofovir disoproxil fumarate, escitalopram, methadone, progestin only contraceptives, raltegravir, warfarin and zolpidem.CLINICAL STUDIESDescription of Clinical Trials
The efficacy and safety of VIEKIRA PAK was evaluated in six randomized, multicenter, clinical trials in 2,308 subjects with genotype 1 (GT1) chronic hepatitis C virus (HCV) infection, including one trial exclusively in subjects with cirrhosis with mild hepatic impairment (Child-Pugh A), as summarized in Table 9.Table 9. Randomized, Multicenter Trials Conducted with VIEKIRA PAK With or Without Ribavirin (RBV) in Subjects with Chronic HCV GT1 Infection

Trial

Population

Study Arms(Number of Subjects Treated)

SAPPHIRE-I
(double-blind)

GT1 (a and b)
TNa without cirrhosis

VIEKIRA PAK + RBV (473)

Placebo (158)

SAPPHIRE-II
(double-blind)

GT1 (a and b)
TEb without cirrhosis

VIEKIRA PAK + RBV (297)

Placebo (97)

PEARL-II
(open-label)

GT1b
TE without cirrhosis

VIEKIRA PAK + RBV (88)

VIEKIRA PAK (91)

PEARL-III
(double-blind)

GT1b
TN without cirrhosis

VIEKIRA PAK + RBV (210)

VIEKIRA PAK (209)

PEARL-IV
(double-blind)

GT1a
TN without cirrhosis

VIEKIRA PAK + RBV (100)

VIEKIRA PAK (205)

TURQUOISE-II
(open-label)

GT1 (a and b)
TN & TE with cirrhosis

VIEKIRA PAK + RBV (12 weeks) (208)

VIEKIRA PAK + RBV (24 weeks) (172)

TN, treatment-naïve was defined as not having received any prior therapy for HCV infection.

In SAPPHIRE-I and -II, subjects without cirrhosis were randomized to VIEKIRA PAK in combination with ribavirin for 12 weeks or to placebo. Subjects in the placebo arm received placebo for 12 weeks, after which they received open-label VIEKIRA PAK in combination with RBV for 12 weeks.

In PEARL-II, -III and -IV, subjects without cirrhosis were randomized to receive VIEKIRA PAK with or without RBV for 12 weeks of treatment.

In the open-label TURQUOISE-II trial, subjects with compensated cirrhosis (Child-Pugh A) who were either treatment-naïve or pegylated interferon/RBV (pegIFN/RBV) treatment-experienced were randomized to receive VIEKIRA PAK in combination with RBV for either 12 or 24 weeks of treatment. Subjects who previously failed therapy with a treatment regimen that included VIEKIRA PAK or other direct-acting antiviral agents were excluded.

In these six clinical trials, the ombitasvir, paritaprevir, ritonavir dose was 25/150/100 mg once daily and the dasabuvir dose was 250 mg twice daily. Doses of drugs in VIEKIRA PAK were not adjusted. For subjects who received RBV, the RBV dose was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighing greater than or equal to 75 kg. RBV dose adjustments were performed according to the RBV labeling.

VIEKIRA PAK with RBV was also evaluated in the following two studies:

HCV GT1-infected liver transplant recipients (CORAL-I).

Subjects with HCV GT1 co-infected with HIV-1 (TURQUOISE-I).

In all eight clinical studies, sustained virologic response was defined as HCV RNA below the lower limit of quantification (<LLOQ) 12 weeks after the end of treatment (SVR12). Plasma HCV RNA levels were measured using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System, which has an LLOQ of 25 IU per mL. Outcomes for subjects not achieving an SVR12 were recorded as on-treatment virologic failure (VF), post-treatment virologic relapse through post-treatment Week 12 or failure due to other non-virologic reasons (e.g., premature discontinuation, adverse event, lost to follow-up, consent withdrawn).

Clinical Trial Results in Adults with Chronic HCV Genotype 1a and 1b Infection without CirrhosisSubjects with Chronic HCV GT1a Infection without Cirrhosis
Subjects with HCV GT1a infection without cirrhosis treated with VIEKIRA PAK with RBV for 12 weeks in SAPPHIRE-I and -II and in PEARL-IV had a median age of 53 years (range: 18 to 70); 63% of the subjects were male; 90% were White; 7% were Black/African American; 8% were Hispanic or Latino; 19% had a body mass index of at least 30 kg per m2; 55% of patients were enrolled in US sites; 72% had IL28B non-CC genotype; 85% had baseline HCV RNA levels of at least 800,000 IU per mL.

Subjects with Chronic HCV GT1b Infection without Cirrhosis
Subjects with HCV GT1b infection without cirrhosis were treated with VIEKIRA PAK with or without RBV for 12 weeks in PEARL-II and -III. Subjects had a median age of 52 years (range: 22 to 70); 47% of the subjects were male; 93% were White; 5% were Black/African American; 2% were Hispanic or Latino; 21% had a body mass index of at least 30 kg per m2; 21% of patients were enrolled in US sites; 83% had IL28B non-CC genotype; 77% had baseline HCV RNA levels of at least 800,000 IU per mL.

Clinical Trial Results in Adults with Chronic HCV Genotype 1a and 1b Infection and Compensated Cirrhosis
TURQUOISE-II was an open-label trial that enrolled 380 HCV GT1a and 1b-infected subjects with cirrhosis and mild hepatic impairment (Child-Pugh A) who were either treatment-naïve or did not achieve SVR with prior treatment with pegIFN/RBV. Subjects were randomized to receive VIEKIRA PAK in combination with RBV for either 12 or 24 weeks of treatment.

Treated subjects had a median age of 58 years (range: 21 to 71); 70% of the subjects were male; 95% were White; 3% were Black/African American; 12% were Hispanic or Latino; 28% had a body mass index of at least 30 kg per m2; 43% of patients were enrolled in US sites; 82% had IL28B non‑CC genotype; 86% had baseline HCV RNA levels of at least 800,000 IU per mL; 69% had HCV GT1a infection, 31% had HCV GT1b infection; 42% were treatment-naïve, 36% were prior pegIFN/RBV null responders; 8% were prior pegIFN/RBV partial responders, 14% were prior pegIFN/RBV relapsers; 15% had platelet counts of less than 90 x 109 per L; 50% had albumin less than 4.0 mg per dL.

Table 11 presents treatment outcomes for GT1 treatment-naïve and treatment-experienced subjects with cirrhosis treated with VIEKIRA PAK with RBV for 12 or 24 weeks in TURQUOISE-II. In GT1a infected subjects, the overall SVR12 rate difference between 24 and 12 weeks of treatment with VIEKIRA PAK with RBV was +6% with 95% confidence interval, -0.1% to +13% with differences varying by pretreatment history.

Table 11. TURQUOISE-II: SVR12 for Chronic HCV Genotype 1-Infected Subjects with Cirrhosis Who Were Treatment-Naïve or Previously Treated with pegIFN/RBV

Effect of Ribavirin Dose Reductions on SVR12
Seven percent of subjects (101/1551) treated with VIEKIRA PAK with RBV had a RBV dose adjustment due to a decrease in hemoglobin level; of these, 98% (98/100) achieved an SVR12. Clinical Trial of Selected Liver Transplant Recipients (CORAL-I)
VIEKIRA PAK with RBV was administered for 24 weeks to 34 HCV GT1-infected liver transplant recipients who were at least 12 months post transplantation at enrollment with normal hepatic function and mild fibrosis (Metavir fibrosis score F2 or lower). The initial dose of RBV was left to the discretion of the investigator with 600 to 800 mg per day being the most frequently selected dose range at initiation of VIEKIRA PAK and at the end of treatment.

Of the 34 subjects (29 with HCV GT1a infection and 5 with HCV GT1b infection) enrolled, (97%) achieved SVR12 (97% in subjects with GT1a infection and 100% of subjects with GT1b infection). One subject with HCV GT1a infection relapsed post-treatment.Clinical Trial in Subjects with HCV/HIV-1 Co-infection (TURQUOISE-I)
In an open-label clinical trial 63 subjects with HCV GT1 infection co-infected with HIV-1 were treated for 12 or 24 weeks with VIEKIRA PAK in combination with RBV. Subjects were on a stable HIV-1 antiretroviral therapy (ART) regimen that included tenofovir disoproxil fumarate plus emtricitabine or lamivudine, administered with ritonavir boosted atazanavir or raltegravir. Subjects on atazanavir stopped the ritonavir component of their HIV-1 ART regimen upon initiating treatment with VIEKIRA PAK in combination with RBV. Atazanavir was taken with the morning dose of VIEKIRA PAK. The ritonavir component of the HIV-1 ART regimen was restarted after completion of treatment with VIEKIRA PAK and RBV.

Treated subjects had a median age of 51 years (range: 31 to 69); 24% of subjects were black; 81% of subjects had IL28B non-CC genotype; 19% of subjects had compensated cirrhosis; 67% of subjects were HCV treatment-naïve; 33% of subjects had failed prior treatment with pegIFN/RBV; 89% of subjects had HCV genotype 1a infection.

The SVR12 rates were 91% (51/56) for subjects with HCV GT1a infection and 100% (7/7) for those with HCV GT1b infection. Of the 5 subjects who were non-responders, 1 experienced virologic breakthrough, 1 discontinued treatment, 1 experienced relapse and 2 subjects had evidence of HCV re-infection post-treatment.

One subject had confirmed HIV-1 RNA >400 copies/mL during the post-treatment period. This subject had no evidence of resistance to the ART regimen. No subjects switched their ART regimen due to loss of plasma HIV-1 RNA suppression.Durability of Response
In an open-label clinical trial, 92% of subjects (526/571) who received various combinations of the direct acting antivirals included in VIEKIRA PAK with or without RBV achieved SVR12, and 99% of those who achieved SVR12 maintained their response through 48 weeks post-treatment (SVR48).
Viekira Pak is marketed by AbbVie Inc., based in North Chicago, Illinois. Olysio is marketed by Raritan, New Jersey-based Janssen Pharmaceuticals. Sovaldi and Harvoni are marketed by Gilead Sciences, based in Foster City, California.
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration

HOW SUPPLIED/STORAGE AND HANDLING
VIEKIRA PAK is dispensed in a monthly carton for a total of 28 days of therapy. Each monthly
carton contains four weekly cartons. Each weekly carton contains seven daily dose packs.
Each child resistant daily dose pack contains four tablets: two 12.5/75/50 mg ombitasvir,
paritaprevir, ritonavir tablets and two 250 mg dasabuvir tablets, and indicates which tablets need
to be taken in the morning and evening. The NDC number is NDC 0074-3093-28.
Ombitasvir, paritaprevir, ritonavir 12.5/75/50 mg tablets are pink-colored, film-coated, oblong
biconvex shaped, debossed with “AV1” on one side. Dasabuvir 250 mg tablets are beige-colored,
film-coated, oval-shaped, debossed with “AV2” on one side.
Store at or below 30°C (86°F).

PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients to review the Medication Guide for ribavirin [see Warnings and Precautions
(5.2)].Risk of ALT Elevations
Inform patients to watch for early warning signs of liver inflammation, such as fatigue,
weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice and
discolored feces, and to consult their health care professional without delay if such symptoms
occur [see Warnings and Precautions (5.1) and Adverse Reactions (6)].
Pregnancy Advise patients to avoid pregnancy during treatment with VIEKIRA PAK with ribavirin. Inform

patients to notify their health care provider immediately in the event of a pregnancy. Inform
pregnant patients that there is an Antiretroviral Pregnancy Registry that monitors pregnancy
outcomes in women who are HCV/HIV-1 co-infected and taking concomitant antiretrovirals [see
Use in Specific Populations (8.1)].

Drug Interactions
Inform patients that VIEKIRA PAK may interact with some drugs; therefore, patients should be
advised to report to their healthcare provider the use of any prescription, non-prescription
medication or herbal products [see Contraindications (4), Warnings and Precautions (5.3) and
Drug Interactions (7)].

Inform patients that the effect of treatment of hepatitis C virus infection on transmission is not
known, and that appropriate precautions to prevent transmission of the hepatitis C virus during
treatment should be taken.

Missed Dose
Inform patients that in case a dose of ombitasvir, paritaprevir, ritonavir is missed, the prescribed
dose can be taken within 12 hours.

In case a dose of dasabuvir is missed, the prescribed dose can be taken within 6 hours.
If more than 12 hours has passed since ombitasvir, paritaprevir, ritonavir is usually taken or more
than 6 hours has passed since dasabuvir is usually taken, the missed dose should NOT be taken
and the patient should take the next dose as per the usual dosing schedule.
Instruct patients not to take more than their prescribed dose of VIEKIRA PAK to make up for a
missed dose.

HCV Education
Review learning activities, editorials, with new data about interferon-free regimens approved for HCV, as well as investigational drugs still in the pipeline. Links are provided to support, patient friendly information, clinical trials, peer-reviewed journals, videos, conferences with commentary, all updated on a continuous basis.

Users can search for a hepatitis C clinical trial by category (genotype), or learn how to evaluate a clinical trial and become familiar with commonly used terms. HCV Advocate offers an easy to navigate HCV Medications Blog as well, organized by HCV genotype

View each rebuttal and all ongoing media coverage. In June the HCV community was blindsided when an article with a somewhat "clickbait" headline was released by The Guardian. The Guardian reported on a systematic review published by the Cochrane Collaboration that suggested achieving SVR (cure) for patients using hepatitis C direct-acting antivirals (DAAs) doesn't correlate with any long term benefits.

The controversy over expensive new drugs for hepatitis C
Link to research and news articles addressing the high cost of hepatitis C drugs; insurance restrictions - private insurers/Medicaid - and availability of generic versions/India, Egypt and other lower-income countries or through online "buyers clubs"

Liver Cancer After Treatment For Hepatitis C
​Research demonstrates that while SVR markedly reduced liver-related complications and liver cancer, some long-term risk for liver cancer remained in those who were cured of Hepatitis C. But after direct-acting antiviral therapy does the risk of developing liver cancer increase?

Meeting Updates

April 19-23
The European Association for the Study of the Liver (EASL) International Liver Congress (ILC 2017)

Merck today announced its strategic decision to discontinue the development of the investigational combination regimens MK-3682B (grazoprevir/ruzasvir/ uprifosbuvir) and MK-3682C (ruzasvir/uprifosbuvir) for the treatment of chronic hepatitis C virus (HCV) infection. This decision was made based on a review of available Phase 2 efficacy data and in consideration of the evolving marketplace and the growing number of treatment options available for patients with chronic HCV infection

Two HCV Drugs to Be Discontinued
The Food and Drug Administration (FDA) announced that Rebetol(ribavirin; Merck) capsules and PegIntron (peginterferon alfa-2b; Merck) for Injection are being discontinued. The decision is business-related and not due to safety or efficacy issues with the drugs.

Rebetol is a nucleoside analogue indicated for chronic hepatitis C in combination with interferon alfa-2b (pegylated and nonpegylated), in patients ≥3 years of age with compensated liver disease. It is supplied as 200mg capsules in 56-, 70-, and 84-count bottles. The Rebetol discontinuation is effective February 1, 2016.
PegIntron is an antiviral indicated for treatment of chronic hepatitis C in patients with compensated liver disease. It is supplied as 50mcg/0.5mL, 80mcg/0.5mL, 120mcg/0.5mL, and 150mcg/0.5mL single-use vials and single-use pre-filled pens. No effective date is available for the PegIntron discontinuation.

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